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Schissel, Carly

Carly Schissel

University of California at Berkely

Talk Title

In-Cell Penetration Selection — Mass Spectrometry Produces Noncanonical Peptides for Antisense Delivery

Presentation Time

Dr. Elizabeth Schram YI Oral Competition
Monday, June 26, 2023, at 04:00 pm - 04:15 pm

Peptide-mediated delivery of macromolecules in cells has significant potential therapeutic benefits, but no therapy employing cell-penetrating peptides, CPPs, has reached the market after 30 years of investigation due to challenges in the discovery of new, more efficient sequences.

Here we demonstrate a method for in-cell penetration selection-mass spectrometry, in-cell PS-MS, to discover peptides from a synthetic library capable of delivering macromolecule cargo to the cytosol. This method was inspired by recent in vivo selection approaches for cell-surface screening, with an added spatial dimension resulting from subcellular fractionation.

abstract image

A representative peptide discovered in the cytosolic extract, Cyto1a, is nearly 100-fold more active toward antisense phosphorodiamidate morpholino oligomer, PMO, delivery compared to a sequence identified from a whole cell extract, which includes endosomes. Cyto1a is composed of D-residues and two non-α-amino acids, is more stable than its all-L isoform, and is less toxic than known CPPs with comparable activity. Pulse-chase and microscopy experiments revealed that while the PMO-Cyto1a conjugate is likely taken up by endosomes, it can escape to localize to the nucleus without nonspecifically releasing other endosomal components. In-cell PS-MS introduces a means to empirically discover unnatural synthetic peptides for subcellular delivery of therapeutically relevant cargo.

Carly received her Ph.D. in Chemistry from the Massachusetts Institute of Technology, where she worked with Prof. Brad Pentelute on both machine learning-guided design and in-cell selection methods to identify sequences for nuclear delivery. She then switched coasts last year and joined the University of California, Berkeley as a Miller Institute Postdoctoral Fellow hosted by Prof. Alanna Schepartz.

Carly's current work focses on generating sequence-defined polymers by expanding the chemical toolkit of native translational machinery. At APS 2023, she is excited to present on her final work in the Pentelute Lab in which she developed a platform for in-cell penetration-selection mass spectrometry, PSMS, to identify fully non canonical peptides that deliver antisense PMO to the nucleus of cells.

Carly Schissel
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